569101
research-article2015
MSJ0010.1177/1352458515569101Multiple Sclerosis JournalSolomon et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Patient perspectives on physician conflict of interest in industry-sponsored clinical trials for multiple sclerosis therapeutics
Multiple Sclerosis Journal 1–7 DOI: 10.1177/ 1352458515569101 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Andrew J Solomon, Eran P Klein, John R Corboy and James L Bernat
Abstract Background: Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. Objective: To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician–industry conflicts of interest created by clinical trials and how such disclosures may influence study participation Methods: An anonymous online instrument was developed. Results: 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients’ decisions to participate in these studies. Conclusions: Findings from this study support a call for uniform guidelines regarding disclosure of physician–industry relationships to prospective research participants for industry-sponsored clinical trials. Keywords: Multiple sclerosis, clinical trials, conflict of interest, professional conduct and ethics, industrysponsored clinical trials Date received: 28 November 2014; accepted: 2 January 2015 Introduction Disclosure of physician–industry financial relationships – such as physician stock ownership or compensation for consultative activities – has become a standard tool for addressing potential physician conflict of interest (COI).1–4 Direct industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials (ISCT) of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician COI. Detailed disclosure of these relationships to potential study participants is not uniformly included as part of informed consent and documentation practices in ISCT. We conducted a survey of multiple sclerosis (MS) patients to understand patient perspectives on the disclosure of physician compensation for participation in ISCT. MS is a
particularly fertile field for the investigation of patient attitudes toward ISCT COI management and disclosure given the rapid development and FDA approval of new therapeutics5 and a global market value for these therapies estimated at up to US$16bn by 2016.6 Methods An anonymous survey instrument of patient attitudes toward physician–industry relationships created by ISCT for MS was developed by the contributing authors and distributed through SurveyMonkey.com to people self-identifying as having MS. The survey directed respondents to questions based on specific responses, and captured an IP address to prevent multiple submissions by a single individual. The survey instrument was not previously validated. The instrument was reviewed by the University of Vermont
Correspondence to: Andrew J Solomon University of Vermont College of Medicine, 1 South Prospect St., Arnold 2, Burlington Vermont, 05401, USA. [email protected] Andrew J Solomon University of Vermont College of Medicine, USA Eran P Klein Oregon Health and Sciences University and Portland VA Medical Center, USA; Department of Philosophy, University of Washington, USA John R Corboy University of Colorado School of Medicine, USA; Denver Veterans Affairs Medical Center, USA James L Bernat Neurology Department, Dartmouth-Hitchcock Medical Center, USA
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Multiple Sclerosis Journal Table 1. Demographic Data For Survey Participants. Gender Age Home State Years since MS diagnosis Had participated in ISCT MS phenotype
Female 82% (453) Male 18% (100) 49.7 +/- 11.9 Oregon 41% (240) Non-Oregon 52% (308) 12.8 +/- 9.8 Yes 13% (76) No 76% (454) Unsure 11%(65) RRMS 75% (397) SPMS 15% (85) PPMS 5% (29) PRMS 3% (15) Unknown 5% (26 )
MS: multiple sclerosis, ISCT: industry sponsored clinical trial, RRMS: relapsing remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis, PPMS: primary progressive multiple sclerosis, PRMS: progressive relapsing multiple sclerosis.
Institutional Review Board prior to use and determined to be exempt from further formal committee review and approval. Recruitment was conducted through posting of an internet link to the survey in the research section of the National Multiple Sclerosis Society (NMSS) website, and regional NMSS chapters publicized the study on their own local websites, through paper or email newsletters, social media, or individual emails to members. Information about the study was also given to patients during routine clinical visits with one of the authors (AJS) at the University of Vermont Medical Center. Study information was given to patients at the Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus in Aurora, Colorado, during routine clinical visits and was also described in a newsletter. The survey was available for completion online exclusively for three months from February 2014 through May 2014. The survey instrument is available as a supplemental file and, because the survey was navigated on the internet and subjects were automatically routed to certain questions, this pdf version of the instrument necessarily contains notation demonstrating the questions displayed to each subject based on their responses.
Results Demographic data Table 1 contains demographic data of survey participants. A total of 597 people with MS participated in the study and 552 completed the entire survey.
Responses from partially completed surveys were included in the results, and questions not answered were coded as missing. The Oregon chapter of the NMSS emailed each member individually about this study while other participating state chapters relied on newsletters and social media. Of the respondents, 41% (240) identified Oregon as their home state, 52% (308) identified one of 36 additional US states as home, and 4 identified regions outside of the US. Given the large number of participants from Oregon, their responses were compared to responses from other states. Statistically significant differences were found in response to demographic questions but in no questions regarding ISCT COI. The mean age for Oregon participants was older (52 vs. 48, p < 0.0001) and their reported mean duration of diagnosis of MS was longer (14.4 years vs. 11.5 years, p = 0.0007). Fewer Oregon respondents identified as having RRMS compared to all other phenotypes of MS (67% vs. 76%, p = 0.0170). Oregon respondents were less likely to have participated in an ISCT (10% vs. 16%, p = 0.02). Responses from subjects who had not participated in an ISCT in the past Of the respondents 76% (454) had not participated in an ISCT for a MS medication in the past and 11% (65) were unsure if they had. For the purpose of analysis, these two groups (“non-ISCT respondents”) were combined. Non-ISCT respondents were given a hypothetical scenario which “offered the opportunity to participate in a pharmaceutical company sponsored research study of a new MS medication at your neurologist’s office.” Among these respondents, 87% (452) thought “a doctor involved in a research study should disclose that they or their office is paid for your participation in the study.” Also, 67% (342) thought “a doctor involved in a research study should disclose how they or their office use money they are paid for your participation in the study.” These results are represented in Table 2 and compared to the cohort of respondents who had participated in an ISCT in the past. When respondents who had not participated in an ISCT in the past were offered participation in a hypothetical ISCT, disclosure of a number of additional COI relationships was also important to their decision whether to participate in the study (Table 3). Of the respondents, 79% (405) thought it was either somewhat important or extremely important “to know if
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AJ Solomon, EP Klein et al. Table 2. MS patients’ opinions regarding disclosure of potential COI for ISCT.
“A doctor involved in a research study should disclose that they or their office is paid for your participation in the study” “A doctor involved in a research study should disclose how they or their office use money they are paid for your participation in the study”
Had not participated in ISCT
Had participated in ISCT
87% (452)
75% (44)
67% (342)
66% (39)
MS: multiple sclerosis, COI: conflicts of interest, ISCT: industry sponsored clinical trial.
Table 3. Importance of disclosure of COI relationships to subjects with MS when considering participation in an ISCT. Potential COI
Disclosure is important
Compensation toward PI salary Previous payments for speaking engagements Previous payments for consulting Current payments for speaking engagements Current payments for consulting
79% (405) 61% (302) 69% (345) 70% (346) 76% (375)
COI: conflicts of interest, MS: multiple sclerosis, ISCT: industry sponsored clinical trial, PI: primary investigator.
the sponsoring pharmaceutical company will because of your participation pay your neurologist money that is used toward their salary” before deciding whether to participate in a study.
past. Of these respondents, 47% (35) participated in the study at a “university,” 23% (17) at a “private practice office,” 15% (11) at a “private research center,” and 16% (12) were “not sure.”
Of the non-ISCT respondents, 61% (302) responded that it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “sometime in the past paid your neurologist to give talks about MS to doctors or patients” before deciding whether to participate in a clinical trial. Of the non-ISCT respondents, 69% (345) responded that it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “sometime in the past paid your neurologist to provide advice (consulting) for the drug company.” Of the non-ISCT respondents, 70% (346) responded that it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “currently pays your neurologist to give talks about MS to doctors or patients,” and 76% (375) responded it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “currently pays your neurologist to provide advice (consulting) for the drug company.”
Of these respondents who had participated in an ISCT, 75% (44) indicated that “a doctor involved in a research study should disclose that they or their office is paid for your participation in the study” and 66% (39) thought “a doctor involved in a research study should disclose how they or their office use the money they are paid for your participation in the study.” These results are displayed in Table 2 and compared to respondents who had not participated in a clinical trial in the past.
Respondents who had participated in an ISCT in the past Of the survey respondents, 13% (76) had “participated in a pharmaceutical company-sponsored research study of a MS medication” sometime in the
Respondents who identified their own neurologist as running the study they enrolled in were asked “Did your neurologist ever discuss whether the pharmaceutical company would provide money to run the study or pay researchers?” Of the respondents, 67% (18) responded “No” and 7% (2) “Not sure.” Among respondents who were enrolled in a study with a neurologist other than their routine care provider, 50% (24) said “No” and 31% (15) did not recall such a discussion. Of those who recalled such a discussion regarding compensation for the ISCT, 53% (10) affirmed that “having this discussion before I enrolled in the study was: important to me/my decision.” Respondents who recalled having a discussion with the primary investigator (PI) about compensation were asked if it was their “understanding that because of your participation
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Multiple Sclerosis Journal money paid to the neurologist running the study would be used: only for ‘overhead’ (such as clinic time and space, staff salaries and supplies) associated with your participation.” Of the respondents, 53% (8) of subjects who had engaged in this conversation thought that compensation would only pay for “overhead.” When asked “Would knowing that the neurologist running the study received money toward their salary from the pharmaceutical company because of your participation have influenced your decision to participate in the study?” 5 (7%) “would probably not have participated” or “would definitely not have participated,” and 13 (18%) chose “not sure,”. When asked “Would it have changed your decision to participate in the study if the pharmaceutical company also had paid the neurologist running the study to give talks about MS to doctors or patients sometime before the study started,” 7 (9%) would “probably not have participated” or “definitely not have participated” and 4 (5%) responded that they “would probably not have participated” or “would definitely not have participated” if the PI was paid to give talks “while you were in the study.” When asked “Would it have changed your decision to participate in the study if the pharmaceutical company also had paid the neurologist running the study to provide advice (consulting) sometime before the study started,” 9 (12%) responded they either “would probably not have participated” or “would definitely not have participated” and 7 (9%) responded they “would probably not have participated” or “would definitely not have participated” if the PI was paid for such “while you were in the study.” Associations Respondents who had not participated in an ISCT in the past were more likely to indicate that they thought “a doctor involved in a research study should disclose that they or their office is paid for your participation in the study,” 87% (452) vs. 75% (44), p = 0.0079. However, respondents who stated they had not participated in an ISCT were just as likely as those who had participated in such a trial to indicate they thought “a doctor involved in a research study should disclose how they or their office use the money they are paid for your participation in the study: 66% (39) vs. 67% (342). Responses to duration of MS diagnosis and type of MS were not significantly associated with responses to any questions surrounding disclosure. In the group that had participated in an ISCT in the past, associations between responses were not assessed given the small number in this group. For respondents who had not participated in an ISCT, women were more likely to respond that it was impor-
tant “to know if the sponsoring pharmaceutical company will because of your participation pay your neurologist money that is used toward their salary”: 81.5% (322) vs. 70.0% (60), p = 0.0146. Women were also more likely to say it was either “somewhat important’ or “very important” “to know that sometime in the past the pharmaceutical company paid your neurologist to give talks about MS to doctors or patients”: 63.3% (250) vs. 47.7% (41), p = 0.0073. Women were also more likely to respond that it was either “somewhat important” or “very important” “to know that sometime in the past the pharmaceutical company paid your neurologist to provide advice (consulting) for the drug company” running the study: 71.14% (281) vs. 60.47% (52), p= 0.0519, when considering an ISCT. Demographic differences noted above between the group of respondents who lived in Oregon compared to non-Oregon respondents did not have a statistically significant influence on the above associations. Discussion ISCT for MS therapeutics involve financial relationships between physicians and industry that lead to improvements in the care of MS patients but that also generate potential COIs. Our study demonstrates the importance of disclosure of information concerning physician COIs in MS ISCT to potential participants, such as who receives compensation, how funds are allocated, and current and prior financial relationships with industry. This perceived importance of COI disclosure is consistent with data from other patient populations.7–13 Our data suggest that the presence of these COIs may influence participation in MS ISCT. Findings from this study support a call for uniform guidelines regarding disclosure of physician–industry relationships to prospective research participants for ISCT. A conflict of interest is “a set of conditions in which professional judgment concerning a primary interest (i.e., a patient’s welfare, validity of research) tends to be unduly influenced by a secondary interest (such as financial gain).”4 Contract research organizations are gradually supplanting academia’s traditional role in drug development, providing new sources of funding for both academic and non-academic physicians.14,15 Budgets for ISCTs are negotiated between sponsors and research institutions or sponsors and individual physician researchers, and can be structured to potentially generate financial surpluses on top of compensation for the time and effort of participating physicians, research staff, and payment of “overhead” expenses.14 In academic centers, such revenue might subsidize various aspects of the research infrastructure,
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AJ Solomon, EP Klein et al. but some benefits may rebound to individual researchers either directly or indirectly and may support productivity or a base salary of a PI, substitute for revenue-generating clinical care, allow for additional protected academic time for other pursuits, or contribute to salaries of the support staff and research coordinators who contribute clinical and academic efforts beyond a particular ISCT. In non-academic settings, the connection between ISCT payment and physician compensation is perhaps more direct.16 The extent to which ISCT as a source of revenue, particularly for private practice physicians, leads to the compromising of ethical standards remains a pressing but open question.16–18 Data on the disclosure of financial relationships to subjects participating in ISCT is limited. The patient populations studied and the specific types of COIs disclosed vary.7–13 Respondents in the present survey overwhelmingly favored disclosure of physician financial relationships. This finding adds to emerging data across diverse disease populations indicating that patients considering participation in clinical trials favor disclosure of physician–industry relationships that may represent a COI.7–13 Potential physician conflicts can be an important piece of information for patients as they weigh the pros and cons of volunteering for a research study and can enhance or preserve trust between a subject and investigator,9,19 and ensure that patients make well-informed decisions that preserve their autonomy. Compensation for ISCT for multiple sclerosis in both academic and nonacademic settings may provide incentives to expand recruitment, but this study suggests that the recruitment benefit may come at a cost. Respondents with MS who had never participated in an ISCT indicated that the presence of a potential COI might influence their decision whether to volunteer for an ISCT. Presented with a hypothetical ISCT, a majority felt it important to know about potential COIs, including a PI’s salary contribution from study involvement as well as whether a PI had current or prior industry financial relationships. Our findings are in agreement with a large study of 5478 potential research participants where a sizeable minority (up to 20%) of respondents indicated they might not participate in a clinical trial if certain financial COIs, particularly individual investigators’ COIs, were present.13 While some studies have suggested that perceived COIs may not impact willingness to participate in research,9–11,19–21 these studies also suggest that disease severity and lack of alternative treatment options, particularly in patients with advanced cancer or who were seriously ill, may
exert a stronger influence on decisions surrounding clinical trial participation.10,11,21 The findings of the current study add to the literature indicating that potential physician COIs in ISCTs may not only increase risk for participants and jeopardize scientific integrity,8,14,19,22 but may also have an adverse effect on recruitment. Our study has several limitations. Our survey instrument was not validated. The authors designed questions to cover many possible forms of potential COIs that might result from financial relationships created by an ISCT. This inclusive and general language may have precluded a more nuanced understanding of the importance of those types of financial arrangements that result in COIs compared to those that do not. We also acknowledge that certain ISCT relationships can result in a net revenue loss for academic departments or practices. As with all surveys there is potential for selection and recall bias, and studies that present hypothetical decisions for respondents are categorically limited. Although participants heard about the study through their neurologist or the National MS Society web site and were presumably diagnosed accurately, there was also no direct ascertainment of diagnostic validity. Responses may have also been influenced by severity of disability and this was not assessed. We carefully worded survey questions in an attempt to use “neutral” language to eliminate bias. This ideal may not always have been met and alternative phrasing of our questions may have led to different results. Moreover, patients carry biases toward the pharmaceutical industry or physician–pharma relationships that may not have been adequately surveyed. Lastly, the subgroup in our study that had participated in an ISCT in the past and completed the survey was small, and more data are needed from those who are currently participating or have participated in ISCT for MS therapies. Collaborations between physicians and industry have resulted in the advancement of scientific knowledge and have improved the care of patients with MS. However, changes in how COIs are disclosed and managed in clinical trials for the development of MS therapeutics are needed. Language in typical consent forms such as “the investigator is being paid by the sponsor to conduct the research study” or “the sponsor will pay the clinic or institution where the study is conducted for the costs of running the study” may not be adequate. Lack of detailed COI disclosure during the consent process risks leaving the impression that compensation will cover only research infrastructure costs, while many of these arrangements allow for a variety of potential secondary
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Multiple Sclerosis Journal gains. Recent attempts to create more detailed disclosure guidelines of COIs for clinical research studies have been published,23,24 but the extent of their implementation is unknown. While many authors have recommended comprehensive and standardized disclosure of investigator relationships with industry, questions about where in the consent process such information is most effectively presented and whether potential subjects are able to understand the implications of these disclosures also need further study.12,19 Avoidance or minimization of potential COIs is the ultimate goal. An important step toward this goal is standardizing and making transparent current physician-industry relationships in ISCTs.1,25,26 Development of disclosure practices for physicians in MS research may provide a model for COI disclosure in ISCT more broadly. Conflict of interest This study was not industry sponsored. Andrew J Solomon received a research grant from the National Multiple Sclerosis Society and was a primary investigator in a multicenter clinical trial for a medication sponsored by Biogen Idec. Eran P Klein has received honoraria for speaking at academic conferences and receives royalty payments for The Birth of Bioethics (Georgetown University Press, 2003). John R Corboy reports that within the last year he was a primary investigator in a multicenter clinical trial for a medication sponsored by Novartis, Sun Pharma, Celgene Therapeutics, the National Multiple Sclerosis Society, and the National Institutes of Health. He has received research grants from the Juvenile Diabetes Research Foundation, the National Multiple Sclerosis Society, and Diogenix. He has served as a consultant for Novartis, Celgene Therapeutics, Teva Neurosciences, and Biogen Idec. He has received honoraria for speaking engagements from Pro CE, Rocky Mountain MS Center, via Genzyme, and for Grand Rounds at multiple academic institutions. He has been compensated for medical-legal work, as an Editor for Neurology: Clinical Practice, and is an uncompensated board member, NMSS ColoradoWyoming Chapter. James L Bernat serves on the editorial boards of Neurocritical Care, Neurology Today, and Multiple Sclerosis and Related Disorders (all unpaid) and the Physician’s Index for Ethics in Medicine (paid). He receives royalty payments for Ethical and Legal Issues in Neurology (Elsevier, 2013), Ethical Issues in
Neurology 3rd ed (Lippincott Williams & Wilkins, 2008), and Palliative Care in Neurology (Oxford University Press, 2004). Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
References 1. Ross JS, Gross CP and Krumholz HM. Promoting transparency in pharmaceutical industry-sponsored research. Am J Public Health 2012; 102: 72–80. 2. Norris SL, Holmer HK, Ogden LA, et al. Conflict of interest disclosures for clinical practice guidelines in the national guideline clearinghouse. PloS one 2012; 7: e47343. 3. Holloway RG, Mooney CJ, Getchius TS, et al. Invited article: Conflicts of interest for authors of American Academy of Neurology clinical practice guidelines. Neurology 2008; 71: 57–63. 4. Thompson DF. Understanding financial conflicts of interest. New Engl J Med 1993; 329: 573–576. 5. GBI Research. Multiple Sclerosis Therapeutics to 2019 – Treatment Diversification, Increasing Efficacy, and Pipeline Innovation Combine to Drive Growth. July 2013. Bolton, UK: GBI. Available at: www.gbiresearch.com 6. IMS Institute for Health Informatics. The Global Use of Medicines: Outlook Through 2016. July 2012. NJ: IMS Inc. Available at: www.imshealth.com 7. Angelos P, Murphy TF, Sampson H, et al. Informed consent, capitation, and conflicts of interest in clinical trials: Views from the field. Surgery 2006; 140: 740–748. 8. Raftery J, Bryant J, Powell J, et al. Payment to healthcare professionals for patient recruitment to trials: Systematic review and qualitative study. Health Technol Assess 2008; 12: 1–128, iii. 9. Tosounidis TI and Kontakis GM. Clinical research: The patients’ perspectives. Injury 2008; 39: 631–635. 10. Gray SW, Hlubocky FJ, Ratain MJ, et al. Attitudes toward research participation and investigator conflicts of interest among advanced cancer patients participating in early phase clinical trials. J Clin Oncol 2007; 25: 3488–3494. 11. Grady C, Horstmann E, Sussman JS, et al. The limits of disclosure: What research subjects want to know about investigator financial interests. J Law Med Ethics 2006; 34: 592–599, 481. 12. Weinfurt KP, Friedman JY, Allsbrook JS, et al. Views of potential research participants on financial conflicts
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AJ Solomon, EP Klein et al. of interest: Barriers and opportunities for effective disclosure. J Gen Intern Med 2006; 21: 901–906. 13. Kim SY, Millard RW, Nisbet P, et al. Potential research participants’ views regarding researcher and institutional financial conflicts of interest. J Med Ethics 2004; 30: 73–79. 14. Hall MA, Friedman JY, King NM, et al. Commentary: Per capita payments in clinical trials: reasonable costs versus bounty hunting. Acad Med 2010; 85: 1554–1556. 15. Shuchman M. Commercializing clinical trials — Risks and benefits of the CRO boom. New Engl J Med 2007; 357: 1365–1368. 16. Fisher JA and Kalbaugh CA. United States privatesector physicians and pharmaceutical contract research: a qualitative study. PLoS medicine 2012; 9: e1001271. 17. Weinfurt KP, Hall MA, Hardy NC, et al. Oversight of financial conflicts of interest in commercially sponsored research in academic and nonacademic settings. J Gen Intern Med 2010; 25: 460–464.
20. Weinfurt KP, Hall MA, Dinan MA, et al. Effects of disclosing financial interests on attitudes toward clinical research. J Gen Intern Med 2008; 23: 860–866. 21. Hampson LA, Agrawal M, Joffe S, et al. Patients’ views on financial conflicts of interest in cancer research trials. New Engl J Med 2006; 355: 2330–2337. 22. Raftery J, Kerr C, Hawker S, et al. Paying clinicians to join clinical trials: a review of guidelines and interview study of trialists. Trials 2009; 10: 15. 23. Rochon PA, Hoey J, Chan AW, et al. Financial conflicts of interest checklist 2010 for clinical research studies. Open Med 2010; 4: e69–91. 24. Weinfurt KP, Hall MA, King NM, et al. Disclosure of financial relationships to participants in clinical research. New Engl J Med 2009; 361: 916–921.
18. Fisher JA. Practicing research ethics: private-sector physicians & pharmaceutical clinical trials. Soc Sci Med 2008; 66: 2495–2505.
25. Ferris LE and Naylor CD. Physician remuneration in industry-sponsored clinical trials: the case for standardized clinical trial budgets. Can Med Assoc J 2004; 171: 883–886.
19. Licurse A, Barber E, Joffe S, et al. The impact of disclosing financial ties in research and clinical care: a systematic review. Arch Intern Med 2010; 170: 675–682.
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research-article2015
MSJ0010.1177/1352458515569101Multiple Sclerosis JournalSolomon et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Patient perspectives on physician conflict of interest in industry-sponsored clinical trials for multiple sclerosis therapeutics
Multiple Sclerosis Journal 1–7 DOI: 10.1177/ 1352458515569101 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Andrew J Solomon, Eran P Klein, John R Corboy and James L Bernat
Abstract Background: Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. Objective: To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician–industry conflicts of interest created by clinical trials and how such disclosures may influence study participation Methods: An anonymous online instrument was developed. Results: 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients’ decisions to participate in these studies. Conclusions: Findings from this study support a call for uniform guidelines regarding disclosure of physician–industry relationships to prospective research participants for industry-sponsored clinical trials. Keywords: Multiple sclerosis, clinical trials, conflict of interest, professional conduct and ethics, industrysponsored clinical trials Date received: 28 November 2014; accepted: 2 January 2015 Introduction Disclosure of physician–industry financial relationships – such as physician stock ownership or compensation for consultative activities – has become a standard tool for addressing potential physician conflict of interest (COI).1–4 Direct industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials (ISCT) of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician COI. Detailed disclosure of these relationships to potential study participants is not uniformly included as part of informed consent and documentation practices in ISCT. We conducted a survey of multiple sclerosis (MS) patients to understand patient perspectives on the disclosure of physician compensation for participation in ISCT. MS is a
particularly fertile field for the investigation of patient attitudes toward ISCT COI management and disclosure given the rapid development and FDA approval of new therapeutics5 and a global market value for these therapies estimated at up to US$16bn by 2016.6 Methods An anonymous survey instrument of patient attitudes toward physician–industry relationships created by ISCT for MS was developed by the contributing authors and distributed through SurveyMonkey.com to people self-identifying as having MS. The survey directed respondents to questions based on specific responses, and captured an IP address to prevent multiple submissions by a single individual. The survey instrument was not previously validated. The instrument was reviewed by the University of Vermont
Correspondence to: Andrew J Solomon University of Vermont College of Medicine, 1 South Prospect St., Arnold 2, Burlington Vermont, 05401, USA. [email protected] Andrew J Solomon University of Vermont College of Medicine, USA Eran P Klein Oregon Health and Sciences University and Portland VA Medical Center, USA; Department of Philosophy, University of Washington, USA John R Corboy University of Colorado School of Medicine, USA; Denver Veterans Affairs Medical Center, USA James L Bernat Neurology Department, Dartmouth-Hitchcock Medical Center, USA
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Multiple Sclerosis Journal Table 1. Demographic Data For Survey Participants. Gender Age Home State Years since MS diagnosis Had participated in ISCT MS phenotype
Female 82% (453) Male 18% (100) 49.7 +/- 11.9 Oregon 41% (240) Non-Oregon 52% (308) 12.8 +/- 9.8 Yes 13% (76) No 76% (454) Unsure 11%(65) RRMS 75% (397) SPMS 15% (85) PPMS 5% (29) PRMS 3% (15) Unknown 5% (26 )
MS: multiple sclerosis, ISCT: industry sponsored clinical trial, RRMS: relapsing remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis, PPMS: primary progressive multiple sclerosis, PRMS: progressive relapsing multiple sclerosis.
Institutional Review Board prior to use and determined to be exempt from further formal committee review and approval. Recruitment was conducted through posting of an internet link to the survey in the research section of the National Multiple Sclerosis Society (NMSS) website, and regional NMSS chapters publicized the study on their own local websites, through paper or email newsletters, social media, or individual emails to members. Information about the study was also given to patients during routine clinical visits with one of the authors (AJS) at the University of Vermont Medical Center. Study information was given to patients at the Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus in Aurora, Colorado, during routine clinical visits and was also described in a newsletter. The survey was available for completion online exclusively for three months from February 2014 through May 2014. The survey instrument is available as a supplemental file and, because the survey was navigated on the internet and subjects were automatically routed to certain questions, this pdf version of the instrument necessarily contains notation demonstrating the questions displayed to each subject based on their responses.
Results Demographic data Table 1 contains demographic data of survey participants. A total of 597 people with MS participated in the study and 552 completed the entire survey.
Responses from partially completed surveys were included in the results, and questions not answered were coded as missing. The Oregon chapter of the NMSS emailed each member individually about this study while other participating state chapters relied on newsletters and social media. Of the respondents, 41% (240) identified Oregon as their home state, 52% (308) identified one of 36 additional US states as home, and 4 identified regions outside of the US. Given the large number of participants from Oregon, their responses were compared to responses from other states. Statistically significant differences were found in response to demographic questions but in no questions regarding ISCT COI. The mean age for Oregon participants was older (52 vs. 48, p < 0.0001) and their reported mean duration of diagnosis of MS was longer (14.4 years vs. 11.5 years, p = 0.0007). Fewer Oregon respondents identified as having RRMS compared to all other phenotypes of MS (67% vs. 76%, p = 0.0170). Oregon respondents were less likely to have participated in an ISCT (10% vs. 16%, p = 0.02). Responses from subjects who had not participated in an ISCT in the past Of the respondents 76% (454) had not participated in an ISCT for a MS medication in the past and 11% (65) were unsure if they had. For the purpose of analysis, these two groups (“non-ISCT respondents”) were combined. Non-ISCT respondents were given a hypothetical scenario which “offered the opportunity to participate in a pharmaceutical company sponsored research study of a new MS medication at your neurologist’s office.” Among these respondents, 87% (452) thought “a doctor involved in a research study should disclose that they or their office is paid for your participation in the study.” Also, 67% (342) thought “a doctor involved in a research study should disclose how they or their office use money they are paid for your participation in the study.” These results are represented in Table 2 and compared to the cohort of respondents who had participated in an ISCT in the past. When respondents who had not participated in an ISCT in the past were offered participation in a hypothetical ISCT, disclosure of a number of additional COI relationships was also important to their decision whether to participate in the study (Table 3). Of the respondents, 79% (405) thought it was either somewhat important or extremely important “to know if
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AJ Solomon, EP Klein et al. Table 2. MS patients’ opinions regarding disclosure of potential COI for ISCT.
“A doctor involved in a research study should disclose that they or their office is paid for your participation in the study” “A doctor involved in a research study should disclose how they or their office use money they are paid for your participation in the study”
Had not participated in ISCT
Had participated in ISCT
87% (452)
75% (44)
67% (342)
66% (39)
MS: multiple sclerosis, COI: conflicts of interest, ISCT: industry sponsored clinical trial.
Table 3. Importance of disclosure of COI relationships to subjects with MS when considering participation in an ISCT. Potential COI
Disclosure is important
Compensation toward PI salary Previous payments for speaking engagements Previous payments for consulting Current payments for speaking engagements Current payments for consulting
79% (405) 61% (302) 69% (345) 70% (346) 76% (375)
COI: conflicts of interest, MS: multiple sclerosis, ISCT: industry sponsored clinical trial, PI: primary investigator.
the sponsoring pharmaceutical company will because of your participation pay your neurologist money that is used toward their salary” before deciding whether to participate in a study.
past. Of these respondents, 47% (35) participated in the study at a “university,” 23% (17) at a “private practice office,” 15% (11) at a “private research center,” and 16% (12) were “not sure.”
Of the non-ISCT respondents, 61% (302) responded that it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “sometime in the past paid your neurologist to give talks about MS to doctors or patients” before deciding whether to participate in a clinical trial. Of the non-ISCT respondents, 69% (345) responded that it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “sometime in the past paid your neurologist to provide advice (consulting) for the drug company.” Of the non-ISCT respondents, 70% (346) responded that it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “currently pays your neurologist to give talks about MS to doctors or patients,” and 76% (375) responded it was either “somewhat important” or “extremely important” to know if a pharmaceutical company “currently pays your neurologist to provide advice (consulting) for the drug company.”
Of these respondents who had participated in an ISCT, 75% (44) indicated that “a doctor involved in a research study should disclose that they or their office is paid for your participation in the study” and 66% (39) thought “a doctor involved in a research study should disclose how they or their office use the money they are paid for your participation in the study.” These results are displayed in Table 2 and compared to respondents who had not participated in a clinical trial in the past.
Respondents who had participated in an ISCT in the past Of the survey respondents, 13% (76) had “participated in a pharmaceutical company-sponsored research study of a MS medication” sometime in the
Respondents who identified their own neurologist as running the study they enrolled in were asked “Did your neurologist ever discuss whether the pharmaceutical company would provide money to run the study or pay researchers?” Of the respondents, 67% (18) responded “No” and 7% (2) “Not sure.” Among respondents who were enrolled in a study with a neurologist other than their routine care provider, 50% (24) said “No” and 31% (15) did not recall such a discussion. Of those who recalled such a discussion regarding compensation for the ISCT, 53% (10) affirmed that “having this discussion before I enrolled in the study was: important to me/my decision.” Respondents who recalled having a discussion with the primary investigator (PI) about compensation were asked if it was their “understanding that because of your participation
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Multiple Sclerosis Journal money paid to the neurologist running the study would be used: only for ‘overhead’ (such as clinic time and space, staff salaries and supplies) associated with your participation.” Of the respondents, 53% (8) of subjects who had engaged in this conversation thought that compensation would only pay for “overhead.” When asked “Would knowing that the neurologist running the study received money toward their salary from the pharmaceutical company because of your participation have influenced your decision to participate in the study?” 5 (7%) “would probably not have participated” or “would definitely not have participated,” and 13 (18%) chose “not sure,”. When asked “Would it have changed your decision to participate in the study if the pharmaceutical company also had paid the neurologist running the study to give talks about MS to doctors or patients sometime before the study started,” 7 (9%) would “probably not have participated” or “definitely not have participated” and 4 (5%) responded that they “would probably not have participated” or “would definitely not have participated” if the PI was paid to give talks “while you were in the study.” When asked “Would it have changed your decision to participate in the study if the pharmaceutical company also had paid the neurologist running the study to provide advice (consulting) sometime before the study started,” 9 (12%) responded they either “would probably not have participated” or “would definitely not have participated” and 7 (9%) responded they “would probably not have participated” or “would definitely not have participated” if the PI was paid for such “while you were in the study.” Associations Respondents who had not participated in an ISCT in the past were more likely to indicate that they thought “a doctor involved in a research study should disclose that they or their office is paid for your participation in the study,” 87% (452) vs. 75% (44), p = 0.0079. However, respondents who stated they had not participated in an ISCT were just as likely as those who had participated in such a trial to indicate they thought “a doctor involved in a research study should disclose how they or their office use the money they are paid for your participation in the study: 66% (39) vs. 67% (342). Responses to duration of MS diagnosis and type of MS were not significantly associated with responses to any questions surrounding disclosure. In the group that had participated in an ISCT in the past, associations between responses were not assessed given the small number in this group. For respondents who had not participated in an ISCT, women were more likely to respond that it was impor-
tant “to know if the sponsoring pharmaceutical company will because of your participation pay your neurologist money that is used toward their salary”: 81.5% (322) vs. 70.0% (60), p = 0.0146. Women were also more likely to say it was either “somewhat important’ or “very important” “to know that sometime in the past the pharmaceutical company paid your neurologist to give talks about MS to doctors or patients”: 63.3% (250) vs. 47.7% (41), p = 0.0073. Women were also more likely to respond that it was either “somewhat important” or “very important” “to know that sometime in the past the pharmaceutical company paid your neurologist to provide advice (consulting) for the drug company” running the study: 71.14% (281) vs. 60.47% (52), p= 0.0519, when considering an ISCT. Demographic differences noted above between the group of respondents who lived in Oregon compared to non-Oregon respondents did not have a statistically significant influence on the above associations. Discussion ISCT for MS therapeutics involve financial relationships between physicians and industry that lead to improvements in the care of MS patients but that also generate potential COIs. Our study demonstrates the importance of disclosure of information concerning physician COIs in MS ISCT to potential participants, such as who receives compensation, how funds are allocated, and current and prior financial relationships with industry. This perceived importance of COI disclosure is consistent with data from other patient populations.7–13 Our data suggest that the presence of these COIs may influence participation in MS ISCT. Findings from this study support a call for uniform guidelines regarding disclosure of physician–industry relationships to prospective research participants for ISCT. A conflict of interest is “a set of conditions in which professional judgment concerning a primary interest (i.e., a patient’s welfare, validity of research) tends to be unduly influenced by a secondary interest (such as financial gain).”4 Contract research organizations are gradually supplanting academia’s traditional role in drug development, providing new sources of funding for both academic and non-academic physicians.14,15 Budgets for ISCTs are negotiated between sponsors and research institutions or sponsors and individual physician researchers, and can be structured to potentially generate financial surpluses on top of compensation for the time and effort of participating physicians, research staff, and payment of “overhead” expenses.14 In academic centers, such revenue might subsidize various aspects of the research infrastructure,
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AJ Solomon, EP Klein et al. but some benefits may rebound to individual researchers either directly or indirectly and may support productivity or a base salary of a PI, substitute for revenue-generating clinical care, allow for additional protected academic time for other pursuits, or contribute to salaries of the support staff and research coordinators who contribute clinical and academic efforts beyond a particular ISCT. In non-academic settings, the connection between ISCT payment and physician compensation is perhaps more direct.16 The extent to which ISCT as a source of revenue, particularly for private practice physicians, leads to the compromising of ethical standards remains a pressing but open question.16–18 Data on the disclosure of financial relationships to subjects participating in ISCT is limited. The patient populations studied and the specific types of COIs disclosed vary.7–13 Respondents in the present survey overwhelmingly favored disclosure of physician financial relationships. This finding adds to emerging data across diverse disease populations indicating that patients considering participation in clinical trials favor disclosure of physician–industry relationships that may represent a COI.7–13 Potential physician conflicts can be an important piece of information for patients as they weigh the pros and cons of volunteering for a research study and can enhance or preserve trust between a subject and investigator,9,19 and ensure that patients make well-informed decisions that preserve their autonomy. Compensation for ISCT for multiple sclerosis in both academic and nonacademic settings may provide incentives to expand recruitment, but this study suggests that the recruitment benefit may come at a cost. Respondents with MS who had never participated in an ISCT indicated that the presence of a potential COI might influence their decision whether to volunteer for an ISCT. Presented with a hypothetical ISCT, a majority felt it important to know about potential COIs, including a PI’s salary contribution from study involvement as well as whether a PI had current or prior industry financial relationships. Our findings are in agreement with a large study of 5478 potential research participants where a sizeable minority (up to 20%) of respondents indicated they might not participate in a clinical trial if certain financial COIs, particularly individual investigators’ COIs, were present.13 While some studies have suggested that perceived COIs may not impact willingness to participate in research,9–11,19–21 these studies also suggest that disease severity and lack of alternative treatment options, particularly in patients with advanced cancer or who were seriously ill, may
exert a stronger influence on decisions surrounding clinical trial participation.10,11,21 The findings of the current study add to the literature indicating that potential physician COIs in ISCTs may not only increase risk for participants and jeopardize scientific integrity,8,14,19,22 but may also have an adverse effect on recruitment. Our study has several limitations. Our survey instrument was not validated. The authors designed questions to cover many possible forms of potential COIs that might result from financial relationships created by an ISCT. This inclusive and general language may have precluded a more nuanced understanding of the importance of those types of financial arrangements that result in COIs compared to those that do not. We also acknowledge that certain ISCT relationships can result in a net revenue loss for academic departments or practices. As with all surveys there is potential for selection and recall bias, and studies that present hypothetical decisions for respondents are categorically limited. Although participants heard about the study through their neurologist or the National MS Society web site and were presumably diagnosed accurately, there was also no direct ascertainment of diagnostic validity. Responses may have also been influenced by severity of disability and this was not assessed. We carefully worded survey questions in an attempt to use “neutral” language to eliminate bias. This ideal may not always have been met and alternative phrasing of our questions may have led to different results. Moreover, patients carry biases toward the pharmaceutical industry or physician–pharma relationships that may not have been adequately surveyed. Lastly, the subgroup in our study that had participated in an ISCT in the past and completed the survey was small, and more data are needed from those who are currently participating or have participated in ISCT for MS therapies. Collaborations between physicians and industry have resulted in the advancement of scientific knowledge and have improved the care of patients with MS. However, changes in how COIs are disclosed and managed in clinical trials for the development of MS therapeutics are needed. Language in typical consent forms such as “the investigator is being paid by the sponsor to conduct the research study” or “the sponsor will pay the clinic or institution where the study is conducted for the costs of running the study” may not be adequate. Lack of detailed COI disclosure during the consent process risks leaving the impression that compensation will cover only research infrastructure costs, while many of these arrangements allow for a variety of potential secondary
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Multiple Sclerosis Journal gains. Recent attempts to create more detailed disclosure guidelines of COIs for clinical research studies have been published,23,24 but the extent of their implementation is unknown. While many authors have recommended comprehensive and standardized disclosure of investigator relationships with industry, questions about where in the consent process such information is most effectively presented and whether potential subjects are able to understand the implications of these disclosures also need further study.12,19 Avoidance or minimization of potential COIs is the ultimate goal. An important step toward this goal is standardizing and making transparent current physician-industry relationships in ISCTs.1,25,26 Development of disclosure practices for physicians in MS research may provide a model for COI disclosure in ISCT more broadly. Conflict of interest This study was not industry sponsored. Andrew J Solomon received a research grant from the National Multiple Sclerosis Society and was a primary investigator in a multicenter clinical trial for a medication sponsored by Biogen Idec. Eran P Klein has received honoraria for speaking at academic conferences and receives royalty payments for The Birth of Bioethics (Georgetown University Press, 2003). John R Corboy reports that within the last year he was a primary investigator in a multicenter clinical trial for a medication sponsored by Novartis, Sun Pharma, Celgene Therapeutics, the National Multiple Sclerosis Society, and the National Institutes of Health. He has received research grants from the Juvenile Diabetes Research Foundation, the National Multiple Sclerosis Society, and Diogenix. He has served as a consultant for Novartis, Celgene Therapeutics, Teva Neurosciences, and Biogen Idec. He has received honoraria for speaking engagements from Pro CE, Rocky Mountain MS Center, via Genzyme, and for Grand Rounds at multiple academic institutions. He has been compensated for medical-legal work, as an Editor for Neurology: Clinical Practice, and is an uncompensated board member, NMSS ColoradoWyoming Chapter. James L Bernat serves on the editorial boards of Neurocritical Care, Neurology Today, and Multiple Sclerosis and Related Disorders (all unpaid) and the Physician’s Index for Ethics in Medicine (paid). He receives royalty payments for Ethical and Legal Issues in Neurology (Elsevier, 2013), Ethical Issues in
Neurology 3rd ed (Lippincott Williams & Wilkins, 2008), and Palliative Care in Neurology (Oxford University Press, 2004). Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
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